Cyclin-dependent kinases (Cdks) are a family of serine/threonine protein kinases playing important cellular functions. The cyclins are the regulatory subunits that activate the catalytic Cdks. Cdk1/Cyclin B1, Cdk2/Cyclin A, Cdk2/Cyclin E, Cdk4/Cyclin D, Cdk6/Cyclin D are critical regulators of cell cycle progression. Cdks also regulate transcription, DNA repair, differentiation, senescence and apoptosis (Morgan D. O., Annu. Rev. Cell. Dev. Biol. 1997; 13:261-291).
Small molecule inhibitors of Cdks have been developed to treat cancer (de Carcer G et al., Curr Med Chem. 2007; 14:969-85). Large amount of genetic evidence support that Cdks play critical roles in the development of most human cancers (Malumbres H. et al, Nature Rev Cancer, 2001; 1:222-231). Genetic alterations in Cdks, their substrates or regulators have been shown to be associated with human cancer. Endogenous protein inhibitors of Cdks including p16, p21 and p27 inhibit Cdk activity and their overexpression result in cell cycle arrest and inhibition of tumor growth in preclinical models (Kamb A., Curr. Top. Microbiolo. Immunol., 1998; 227:139-148).
Small molecule inhibitors of Cdks may also be used to treat variety of other diseases that result from aberrant cell proliferation, including cardiovascular disorders, renal diseases, certain infectious diseases and autoimmune diseases. Cell proliferation regulatory pathways including genes involved in the cell cycle G1 and S phase checkpoint (p53, pRb, p15, p16, and Cyclins A, D, E, Cdk 2 and Cdk4) have been associated with plaque progression, stenosis and restenosis after angioplasty. Over-expression of the Cdk inhibitor protein p21 has been shown to inhibit vascular smooth muscle proliferation and intimal hyperplasia following angioplasty (Chang M. W. et al., J. Clin. Invest., 1995; 96:2260; Yang Z-Y. et al., Proc. Natl. Acad. Sci. (USA) 1996; 93:9905). A small molecule Cdk2 inhibitor CVT-313 (Ki=95 nM) was shown to cause in significant inhibition of neointima formation in animal models (Brooks E. E. et al., J. Biol. Chem. 1997; 272:29207-29211). Disregulation of cell cycle has been associated with polycystic kidney diseases, which are characterized by the growth of fluid-filled cysts in renal tubules. Treatment with small molecule inhibitors of Cdks yielded effective arrest of cystic disease in mouse models (Bukanov N. O., et al., Nature, 2006; 4444:949-952). Infection by a variety of infectious agents, including fungi, protozoan parasites such as Plasmodium falciparum, and DNA and RNA viruses may be treated with Cdk inhibitors. Cdks have been shown to be required for replication of herpes simplex virus (HSV) (Schang L. M. et al., J. Virol. 1998; 72:5626). Cdks are essential proteins in yeast. Synovial tissue hyperplasia plays important roles in the development of rheumatoid arthritis; inhibition of synovial tissue proliferation may suppress inflammation and prevent joint destruction. It has been shown that over-expression of Cdk inhibitor protein p16 inhibited synovial fibroblast growth (Taniguchi K. et al., Nat. Med. 1999; 5:760-767) and joint swelling was substantially inhibited in animal arthritis models.
Selective inhibitors of some Cdks may also be used to protect normal untransformed cells by inhibiting specific phases of cell cycle progression (Chen et al. J. Natl. Cancer Institute, 2000; 92:1999-2008). Pre-treatment with a selective Cdk inhibitor prior to the use of a cytotoxic agent that inhibits a different phase of the cell cycle may reduce the side effects associated with the cytotoxic chemotherapy and possibly increase the therapeutic widow. It has been shown that induction of cellular protein inhibitors of Cdks (p16, p27 and p21) conferred strong resistance to paclitaxel- or cisplatin-mediated cytotoxicity on the inhibitor-responsive cells but not on the inhibitor-unresponsive cells (Schmidt, M, Oncogene, 2001 20:6164-71).